Abstract TP349: Deleted NLRP3 inflammasome improves functional outcome and improves cerebral blood flow in an experimental model of Vascular Cognitive Impairment and Dementia

Background: Inflammation, a key player in both acute and chronic cerebral ischemia, is activated in brain tissues by bilateral carotid stenosis (BCAS)- induced chronic cerebral hypoperfusion. Our study aimed to investigate whether the deletion of the NLRP3inflammasome could abolish the deleterious effects of BCAS-induced chronic hypoperfusion in an experimental model of VCID. Methods: Microcoil-induced BCAS was used to induce chronic hypoperfusion. Middle-young (8-10 mice per group,4-5 months old, male) NLRP3WT and NLRP3KO were randomly assigned to BCAS-induced chronic hypoperfusion for four weeks. Cerebral blood flow was measured by laser speckle contrast imaging (LCSI) and CBF-ASL perfusion by MRI, and novel object recognition (NOR) and wire-hanging tests were also measured. Biochemical and histopathological staining was also assessed on the brain tissues. Results: At four weeks, there was a significant increase in CBF by LSCI and CBF-ASL perfusion by MRI in NLRP3KO mice compared to NLRP3WT groups. More importantly, the cognitive and motor function, as measured by NOR and wire-hanging tests, showed a remarkable improvement in NLRP3KO mice compared to WT. Conclusions: The findings suggest that deletion of NLRP3 inflammasome not only mitigates the cognitive impairment and motor effects of chronic hypoperfusion but also significantly improves cerebral blood flow. This indicates that targeting the NLRP3 inflammasome may be a new therapeutic approach against VCID.